Overexpressed IGF-I Receptors Reduce Estrogen Growth Requirements, Enhance Survival, and Promote E-Cadherin-Mediated Cell–Cell Adhesion in Human Breast Cancer Cells

Guvakova, Marina A.; Surmacz, Ewa

doi:10.1006/excr.1996.3457

Cited by 132 publications

(101 citation statements)

References 28 publications

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“…This complex also contains the IGF-IR, as described in our previous work (7,8). Here, we analyzed tyrosine phosphorylation status of the IGF-IR, E-cad, and ZO-1, and the interactions among these proteins in MCF-7 and MCF-7/IGF-IR cells cultured as three-dimensional spheroids (Fig.…”

Section: Interactions Of Zo-1 With the E-cad Complex In Mcf-7/ Igf-irmentioning

confidence: 80%

“…The experimental data suggest that the IGF-IR has a function in cell spreading by effectively stimulating the motility of different metastatic breast cancer cell lines lacking the expression of a major adhesion protein, E-cadherin (E-cad) (1,5,6). On the other hand, we and others have shown that in more differentiated E-cad-positive cells, IGF-I treatment or IGF-IR overexpression up-regulates cell-cell adhesion, which correlates with increased cell survival in three-dimensional culture and with reduced cell migration in vitro and in organ culture (1,(7)(8)(9)(10).…”

mentioning

confidence: 88%

“…Previously, we demonstrated that in MCF-7 human breast cancer cells, the IGF-IR co-localizes and co-precipitates with the E-cad complex and that IGF-induced aggregation is blocked with an anti-E-cad antibody (7). In this study we assessed the effects of the IGF-IR on the elements of the E-cad adhesion complex, i.e.…”

mentioning

confidence: 98%

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IGF-I Receptor-induced Cell-Cell Adhesion of MCF-7 Breast Cancer Cells Requires the Expression of Junction Protein ZO-1

Mauro¹,

Bartucci²,

Morelli³

et al. 2001

Journal of Biological Chemistry

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Hyperactivation of the insulin-like growth factor I receptor (IGF-IR) contributes to primary breast cancer development, but the role of the IGF-IR in tumor metastasis is unclear. Here we studied the effects of the IGF-IR on intercellular connections mediated by the major epithelial adhesion protein, E-cadherin (E-cad). We found that IGF-IR overexpression markedly stimulated aggregation in E-cad-positive MCF-7 breast cancer cells, but not in E-cad-negative MDA-MB-231 cells. However, when the IGF-IR and E-cad were co-expressed in MDA-MB-231 cells, cell-cell adhesion was substantially increased. The IGF-IR-dependent cell-cell adhesion of MCF-7 cells was not related to altered expression of E-cad or ␣-, ␤-, or ␥-catenins but coincided with the up-regulation of another element of the E-cad complex, zonula occludens-1 (ZO-1). ZO-1 expression (mRNA and protein) was induced by IGF-I and was blocked in MCF-7 cells with a tyrosine kinase-defective IGF-IR mutant. By co-immunoprecipitation, we found that ZO-1 associates with the E-cad complex and the IGF-IR. High levels of ZO-1 coincided with an increased IGF-IR/␣-catenin/ZO-1-binding and improved ZO-1/actin association, whereas down-regulation of ZO-1 by the expression of an anti-ZO-1 RNA inhibited IGF-IR-dependent cell-cell adhesion. The results suggested that one of the mechanisms by which the activated IGF-IR regulates E-cad-mediated cell-cell adhesion is overexpression of ZO-1 and the resulting stronger connections between the E-cad complex and the actin cytoskeleton. We hypothesize that in E-cad-positive cells, the IGF-IR may produce antimetastatic effects.

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Section: Interactions Of Zo-1 With the E-cad Complex In Mcf-7/ Igf-irmentioning

confidence: 80%

mentioning

confidence: 88%

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IGF-I Receptor-induced Cell-Cell Adhesion of MCF-7 Breast Cancer Cells Requires the Expression of Junction Protein ZO-1

Mauro¹,

Bartucci²,

Morelli³

et al. 2001

Journal of Biological Chemistry

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“…IGF-I and IGF-II are produced by breast cancer cell lines (17,18), and administration of IGFs to breast cancer cells promotes cell proliferation and inhibits apoptosis (19,20). IGFs are known to mediate their cellular effects, at least in part, through the PI3K pathway (19).…”

Section: Thus We Have Identified a Novel Negative Feedback Loop Withmentioning

confidence: 99%

Insulin-like Growth Factor-II Regulates PTEN Expression in the Mammary Gland

Moorehead

Hojilla

Belle

et al. 2003

Journal of Biological Chemistry

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The tumor suppressor PTEN is altered in many cancers, including breast cancer, but only a handful of factors are known to control its expression. PTEN plays a vital role in cell survival and proliferation by regulating Akt phosphorylation, a key component of the phosphatidylinositol 3 kinase (PI3K) pathway. Here we show that insulin-like growth factor-II (IGF-II), which signals through PI3K, regulates PTEN expression in the mammary gland. IGF-II injection into mouse mammary gland significantly increased PTEN expression. Transgenic IGF-II expression also increased mammary PTEN protein, leading to reductions in Akt phosphorylation, epithelial proliferation, and mammary morphogenesis. IGF-II induced PTEN promoter activity and protein levels and this involved the immediate early gene egr-1. Thus, we have identified a novel negative feedback loop within the PI3K pathway where IGF-II induces PTEN expression to modulate its physiologic effects.PTEN 1 is emerging as the most frequently altered tumor suppressor gene other than p53 (1). PTEN is mutated in Cowden's syndrome, a condition of familial cancer predisposition, and is frequently altered in a variety of spontaneous cancers including breast cancers (2-4). The loss of even one PTEN allele in mice leads to a high incidence of tumors in a variety of tissues (3,5). Breast cancer in humans is associated with a loss of heterozygosity or mutation of the PTEN gene, and decreased PTEN expression has been associated with invasive breast cancer and poor prognosis (2, 6, 7). The principal activity of PTEN is to dephosphorylate a phospholipid second messenger, phosphatidylinositol 3,4,5-triphosphate (PIP3), produced by phosphatidylinositol 3 kinase (PI3K) (8, 9). PIP3 is the major activator of the cell survival kinase Akt (8, 9). Thus, negative regulation of the PI3K pathway by PTEN is critical, and the loss of PTEN function creates an environment conducive to tumorigenesis.Despite the obvious importance of PTEN, only a handful of molecules are known to control its expression. Intracellular molecules reported to regulate PTEN transcription include p53 (10), peroxisome proliferator-activated receptor ␥ (11) and Egr-1 (12). These proteins induce PTEN promoter activity and putative binding sites for each have been identified in the PTEN promoter. Transforming growth factor ␤ and progesterone have also been proposed to alter PTEN expression. Transforming growth factor ␤ inhibited PTEN expression, but the nature of this regulation is unknown (13). Endometrial PTEN levels were higher during the secretory compared with the proliferative phase of the menstrual cycle implying an association with progesterone levels (14). Given the critical role of PTEN in the control of cell survival and proliferation, it stands to reason that extracellular factors such as hormones or growth factors should also influence PTEN expression.Insulin-like growth factors (IGFs) are potent mitogens that impact development, are implicated as risk factors in breast cancer, and are overexpressed in human cancers (...

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“…22 However, a recent study has shown that overexpression of the IGF-IR promotes aggregation, growth, and cell survival in MCF-7 human breast cancer cells. 23 Therefore, our hypothesis was that IGF-IR played a role in human metastatic breast cancer, and that cancer cells treated with a stable antisense IGF-IR-expressing construct have a decreased probability of forming metastases.…”

mentioning

confidence: 99%

Treatment of human breast cancer cells with antisense RNA to the type I insulin-like growth factor receptor inhibits cell growth, suppresses tumorigenesis, alters the metastatic potential, and prolongs survival in vivo

Chernicky

Tan

et al. 2000

Cancer Gene Ther

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The type I insulin-like growth factor receptor (IGF-IR) plays an important role in the growth and transformation of breast cancer cells. In this study, we investigated the effects of treatment with an antisense IGF-IR construct on cells from the highly metastatic estrogen receptor-negative human breast cancer cell line MDA-MB-435s. The cells carrying the antisense IGF-IR had a markedly reduced expression of IGF-IR, had a significant decrease in cell proliferation, and lost the ability to form colonies in soft agar. There was a delay in tumor formation and a dramatic reduction in tumor size when cells carrying the antisense IGF-IR were injected into either nude or severe combined immunodeficient (scid) beige mice. We have also provided data that show that the scid beige mouse is a more suitable model for studying metastasis of the MDA-MB-435s cells. All of the scid beige mice injected with cells carrying the control construct had metastasis to the lungs, whereas lungs from the nude mice had no apparent metastatic sites after 11 weeks. When cells carrying antisense IGF-IR were injected subcutaneously in scid beige mice, the animals had a significant increase in survival compared with mice injected with cells carrying the control construct. Taken together, these results indicate that the IGF-IR can play a critical role in the progression of breast cancer. Our studies provide a basis for the development of future treatment strategies targeting the IGF-IR in metastatic breast cancer. Cancer Gene Therapy (2000) 7, 384 -395

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Overexpressed IGF-I Receptors Reduce Estrogen Growth Requirements, Enhance Survival, and Promote E-Cadherin-Mediated Cell–Cell Adhesion in Human Breast Cancer Cells

Cited by 132 publications

References 28 publications

IGF-I Receptor-induced Cell-Cell Adhesion of MCF-7 Breast Cancer Cells Requires the Expression of Junction Protein ZO-1

IGF-I Receptor-induced Cell-Cell Adhesion of MCF-7 Breast Cancer Cells Requires the Expression of Junction Protein ZO-1

Insulin-like Growth Factor-II Regulates PTEN Expression in the Mammary Gland

Treatment of human breast cancer cells with antisense RNA to the type I insulin-like growth factor receptor inhibits cell growth, suppresses tumorigenesis, alters the metastatic potential, and prolongs survival in vivo

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